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Med Gen Section 3 > Connective Tissue/Skeletal Dysplasia/Collagenopathies > Flashcards

Connective Tissue/Skeletal Dysplasia/Collagenopathies Flashcards

1
Q

List the disorders of fibrillin-TGFbeta pathway.

A

Marfan Syndrome

Loeys-Deitz Syndrome

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2
Q

List the disorders of collagen production and assembly.

A

Ehlers Danlos Syndrome
Osteogenesis Imperfecta
Stickler Syndrome

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3
Q

What is Marfan Syndrome?

A

AD
mutations in FBN1 gene with complete penetrance (though normally age related)
25% spontaneous mutations

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4
Q

What is the 2010 Ghent criteria?

A 
used to diagnose Marfan Syndrome
without family history
Ao (Z>2) + Ectopia Lentis
Ao (Z>2) + FBN1 mutation
Ao (Z>2) + Systemic score (>7 points)
Ectopia Lents + FBN1 known Ao
with family history
one of (Ectopia lentis, systemic score >7 points, Ao (Z>2 above 20, >3 below 20yo)
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5
Q

What contributes to the Marfan Syndrome systemic score?

A 
pectus excavotum/pigeon (1-2 points)
wrist/thumb signs (1-3 points)
pneumothorax (2 points)
armspan/height or US/LS (1)
scoliosis/kyphosis (1)
myopia (>3 dpts)
facial features (1 each)
dural ectasia (2)
food deformity/pes planus (1-2)
elbow extension decreased (1)
skin striae (1)
protrusio acetabulae (2)
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6
Q

What are the most common phenotypes associated with Marfan syndrome?

A

ectopia lentis (bilateral, symmetrical, and superotemporal/upsloping)
other ocular abnormalities (myopia, retinal detachment, glaucoma)
progressive aortic dilation
other cardiac (MVP, MR, TR, enlarged pulmonary artery)
dural ectasia
dolichostenomelia
arachnodactyly

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7
Q

What is Neonatal Marfan Syndrome?

A

severe early presentation of symptoms
50% mortality by 1st year (due to severe mitral valve regulation and heart failure)
most de novo mutations (exons 24-32)

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8
Q

What fetal US findings are associated with Neonatal Marfan Syndrome?

A 
arachnodactyly
joint contractures
AV valve insufficiency
worsening cardiomegally
dilated pulmonary and aortic roots
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9
Q

What other conditions have FBN1 mutations but do not meet the Ghent criteria?

A

MASS phenotype
Mitral valve prolapse
Familial ectopia lentis
Thoracic aortic aneurysm

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10
Q

How is Marfan Syndrome managed?

A

restriction of contact/competitive sports and isometric exercise
surveillance (annual or more frequent CT/MRA in adults for cardiology to assess aorta size)
medications (beta blockers; losartan)
surgical repair
avoide LASIK and SCUBA procedures

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11
Q

How is Marfan Syndrome managed in females who are or are planning to become pregnant?

A

pre-pregnancy ECHO with monitoring every 2-3 months
aortic diameter <40mm and minimal cardiac disease do well
1% risk of endocarditis, dissection, heart failure
10% risk if aortic diameter is >40mm (>47 repair recommended)
beta blockers
consult with anesthesiology (dural ectasia could complicate epidural)
15% prematurity (20-32 weeks)due to PRM, cervical insufficiency, or maternal cardiac status
no increased fetal morbidity

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12
Q

What conditions would be included on a DDx for symptoms of Marfan syndrome?

A 
Loeys-Deitz
Congenital Contractural Arachnodactyly
Familial or Hereditary Thoracic Artery Aneurysms and Disection (FTAAD or HTAD)
Shprintzen-Goldberg
Homocystenuria
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13
Q

What symptoms over lap between Marfan Syndrome and Homocystenuria?

A

ectopia lentis (homocystenuria is downslanting)
myopia
tendency to thrombosis
failure to thrive in newborns and/or developmental delay
tall stature with long, thin limbs and fingers
chest deformaties
scoliosis

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14
Q

What symptoms are associated with Loeys-Dietz Syndrome 1?

A 
facial dysmporphism
cleft palate
bifid uvula
cranisynostosis
micrognathia
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15
Q

What symptoms are associated with Loeys-Deitz Syndrome?

A

EDS-like with bruising, poor scaring, joint laxity, and visceral rupture
newer phenotypic findings include facial milia, IBD, eosinophilic esophagitis

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16
Q

What symptoms are associated with Loeys-Deitz Syndrome in general?

A

aortic root aneurysm (common, early rupture at small diameters- 50% will have at other locations)
bicuspid aortic valve
arterial tortuosity (head and neck vessels)
dissection of vessels in thoracic region
average age at first surgery:13 y/o
average age at death: 26 y/o
increased risk of uterine rupture in pregnancy

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17
Q

What is Loeys-Deitz syndrome?

A 
AD
75% new mutations
TGFBR1 and TGFBR2 (55-60%)
SMAD3 (osteoarthritis)
TGFB2 and TGFB3 (milder)
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18
Q

What other conditions result from mutations in FBN1?

A

Weill Marchesani
Geleophysical dysplasia
Acrommicric dysplasia

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19
Q

List the disorders of collagen production and assembly and which type of collagen the affect.

A

Type I: Osteogenesis Imperfecta
Type II, IX, and XI: Stickler Syndrome
Type III: Vascular Ehler’s Danlose Syndrome
Type V: Classic Ehler’s Danlose Syndrome

20
Q

What is Ehler’s Danlose Syndrome?

A

mostly AD
heterogenous group of disorders
best known subtypes include classic, hypermobile, adn vascular

21
Q

What are the symptoms consistent across all subtypes of Ehler’s Danlose Syndrome?

A

skin hyperextensibility
joint hypermobility
connective tissue fragility

22
Q

Describe the vascular subtype of EDS.

A

COL3A1 gene (encodes type III procollagen homotrimer in skin, blood vessels, and organs)
accounts for 4% of all EDS
most severe with high mortality
hard to diagnose without a genetic test
mean age of death is 48y/o presenting with to acute abdomen, retroperitoneal hemorrhage, and sudden collapse/shock

23
Q

What are the major clinical diagnostic criteria for vascular EDS?

A 
arterial rupture (young age)
intestinal rupture
uterine rupture
family history of vascular EDS with documented mutation
AV fistula (carotid-cavernous sinus)
24
Q

What are the minor clinical diagnostic criteria for vascular EDS?

A 
skin bruising/translucency
facial appearance
acrogeria
hypermobility of small joints
tendon/muscle rupture
pneumothorax
joint subluxation/dislocations
CHD/club foot
varicose veins
gingival recession
keratoconus
25
Q

What other symptoms are present with vascular EDS?

A

mitral valve prolapse
strokes and progressively dilating aneurysms (less common)
GI issues (sigmoid perforations)
uterine rupture in perinatal period
pregnancy related complications
inguinal hernias, pneumothorax, and/or joint dislocations in childhood

26
Q

How is vascular EDS managed?

A

avoid contact/competitive sports and isomeric exercise
anticoagulation contraindicated
DON’T stick needles in arteries
elective surgery increases complication rates
beta blockers or celiprolol questionable
possible surveillance with MRA/MRI
medical alert bracelets
11.5% maternal mortality (due to uterine rupture)

27
Q

Describe classic EDS.

A

COL5A1/COL5A2 mutants resulting in type V collagen defect (90% of patients)
complete lack of Tenascin XB (TNX gene)

28
Q

How is classic EDS diagnosed?

A 
skin hyperextensibility and atrophic scarring with joint hypermobility and/or at least three of the following (minor criteria):
family history
bruising
soft skin
fragility
hernia
29
Q

Describe the hypermobile form of EDS.

A

clinical diagnosis ONLY because basically no genes
criteria is the Beighton scale which requires >5.. plus two of the following:
5+ symmetric feature
positive family history
musculoskeletal (pain and medically confirmed dislocations/instability)
EXCLUDES:
unusual fragility/rheumatological or other alternative diagnosis such as neuromuscular, etc

30
Q

What disorders other than EDS affect the ascending aorta?

A

FTAAD (Familial aortic aneurysm and dissection)

31
Q

What kinds of testing is available for EDS?

A

biochemical/genetic testing with skin fibroblasts (secrete connective tissue proteins so you can quantitatively and qualitatively assay for abnormal collagen or fibrillin by electrophoresis- this is rare) or NGS (COL5A1/COL5A2, COL3A1, COL1A1/COL1A2 or single gene testing with del/dup)

32
Q

What is Osteogenesis Imperfecta?

A

AD (collagen-related subtypes) AR (non-collagen subtypes- only 10-15%)
COL1A1 or COL1A2
abnormal collagen microfibril assembly
4 common subtypes

33
Q

List the most common collagen-related subtypes of Osteogenesis Imperfecta.

A 
Type I (50%): blue sclera, normal height, fractures, hearing loss, DI rare
Type II (severe): perinatal lethality, limb defects, blue-grey sclera, soft calvarium, multiple fractures
Type III (severe): fractures, deformities, early hearing loss, DI, progressive
Type IV: normal sclera, DI common, adult hearing loss, milder than III
34
Q

How is Osteogenesis Imperfecta managed?

A 
orthopedic
PT
psychosocial
bisphosphinates (to improve mineralization)
screenings for hearing loss
dental screenings
35
Q

Describe the continuum of syndromes/phenotypes for Type II Collagenopathies.

A

skeletal dysplasia (severe disproportionate short stature)
ocular (retinal and myopia)
hearing loss (mixed)
orofacial (flat facies, Pierre Robin sequence, cleft palate, laryngomalacia)

36
Q

List the Type II Collagenopathies.

A

Achondrogenesis type II (lethal)
Kneist, SEDC (severe)
SED, Stickler type I (intermediate)
SED with arthritis (mild)

37
Q

What is Stickler Syndrome?

A 
COL2A1 (80-90%) and COL11A1 (10-20%) results in ocular, mild hearing loss, joint involvement
rare COL11A2 (non-ocular form) and COL9A1/COL9A2 (recessive forms)
38
Q

What symptoms are associated with Stickler Syndrome?

A

eye (early onset cataracts, vitreous anomaly, retinal detachment, myopia, >3D)
craniofacial (depressed nasal bridge, bifid uvula or cleft palate, Robin sequence)
hearing (sensorineural/conductive hearing loss)
joint disease (hypermobility, osteoarthritis, spondyloepiphyseal dysplasia)

39
Q

List the perinatal lethal skeletal dysplasias.

A

FGFR3 (Thanatophoric dysplasia- AD)
Type 2 Collagenopathy (Achondrogenesis II, hypochondrogenesis- AD)
Sulfation disorder (achondrogenesis 1B- AR)
Short Rib-Polydactyly syndromes (AR)
Osteogenesis Imperfecta Type 2 (AD)
Campomelia dysplasia (AD) or XY DSD

40
Q

What is Thanatophoric Dysplasia?

A

TD1 or TD2

most common neonatal lethal dysplasia

41
Q

What phenotype is associated with Thanatophoric Dysplasia?

A 
shortened and or bowed limbs
platyspondyly
narrow chest with protuberant abdomen
short ribs
macrocrania with frontal bossing +/- hydrocephalus
cloverleaf skull
polyhydramnios
redundant, thickened soft tissues
CNS abnormalities (mild ventriculomegaly, posterior fossa hypoplasia, temporal lobe abnormalities)
42
Q

What is Achondroplasia?

A 
AD
most common non-lethal dysplasia
FGFR3 mutations
fully penetrant
80% de novo
paternal origin
homozygous cases are lethal but can have compound hets with other genes
43
Q

What features at birth are indicative of Achondroplasia?

A 
macrocephally
sleep apnea
frontal bossing
cervical cranial junction
rhizomelia and other segments
trident hands (splaying of digits 3 and 4)
lordosis, bowing
hydrocephalus
spinal stenosis
abnormal radiological findings
44
Q

List the FGFR3 Related Disorders.

A 
Hypochondroplasia
Thanatopheric dysplasia
Craniosynostosis
SADDAN
Homozygous Achondroplasia mutations
45
Q

What are common features of Skeletal Ciliopathies?

A

narrow chest
short limbs
short ribs
polydactyly

46
Q

List examples of Skeletal Ciliopathies.

A

Cranioectodermal dysplasia

Ellis van Creveid

47
Q

What are Skeletal Ciliopathies?

A

AR

defects in non-motile cilia (primary cilia)

Med Gen Section 3 (13 decks)

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